Vascular diseases, in particular atherosclerosis and its complications (e.g., myocardial infarction and stroke), continue to be a major public health problem that afflicts millions of people in the United States and other countries. Given their inherently complex and variable nature, the study of monogenic forms of some types of vascular disease (e.g., familial hyperlipidemias and atherosclerosis) can greatly assist in elucidating their pathogenesis. The recent discovery of the genetic basis of Hutchinson-Gilford Progeria Syndrome (HGPS) provides such an opportunity. HGPS is a premature aging disorder in which affected children have normal appearance at birth, but begin to age rapidly within 1-2 years. This disease affects multiple organ systems, including the heart and blood vessels. Indeed, the most prominent and fatal feature of HGPS is premature and accelerated atherosclerosis resulting in heart attacks and strokes. HGPS is caused by a single point mutation in the LMNA gene, which results in accumulation of a mutant form of the lamin A protein called Progerin. The central hypothesis of this project is that Progerin accumulation in vascular endothelium results in chronic endothelial dysfunction, contributing to the onset of vascular pathologies documented in patients with HGPS, and potentially also in normal individuals with aging. In the first specific aim, we will dissect the molecular pathways activated in Progerin-expressing cultured EC that lead to chronic endothelial dysfunction. In the second specific aim, we will elucidate the paracrine effects that endothelial-derived, Progerin- stimulated mediators (such as interleukin-1) exert on vascular smooth muscle cells. In the third specific aim, we will investigate the pathophysiological consequences of endothelial-specific expression of Progerin in vivo in a novel transgenic murine model. These studies should provide important mechanistic insights into the cellular and molecular causes of vascular disease in HGPS patients, and may suggest new therapeutic strategies for other vascular diseases in which endothelial dysfunction plays a pathogenic role.